It is known that the concentration of nitric oxide (NO) in exhaled air can be used as an indicator of various pathological conditions. For instance, the concentration of exhaled nitric oxide (eNO) is a non-invasive marker for airway inflammation. Inflammation of the airways is typically present in people with asthma and monitoring for high concentrations of eNO can be used in a test which is useful in identifying asthma. Furthermore, measurements of eNO can be used for monitoring the effectiveness of inhaled corticosteroids (ICS) and in anti-inflammatory asthma management to titrate ICS dosage.
The standardized method of measuring eNO requires a single exhalation test at a fixed flow rate of 50 ml/s at an overpressure of at least 5 cm H2O. The exhalation test requires a constant exhalation flow for a given period of at least 10 seconds, and is not simple to perform by those with breathing difficulties or by young children. Therefore, conventional devices make use of visual and acoustic feedback signals to guide the user through the test successfully. Commercially available systems from Aerocrine and Apieron have received U.S. FDA approval for standardized eNO measurements in children aged 7-18 years and adults under supervision of a trained operator in a physician's office. No FDA-approved system for young children is currently available.
It is clear that a more straightforward and natural breathing procedure (for example tidal breathing) would be more preferable for young children and for non-professional (i.e. home) use.
It has been proposed in EP application no. 09166814.5 to measure the flow rate and eNO during an exhalation and subsequently analyze the measured data using a model that describes the generation and transport of NO in the airway system. In this way, flow-independent parameters can be deduced from tidal breathing patterns and if necessary, the value at 50 ml/s used in the standardized method can be derived.
An apparatus has been developed that measures eNO with a NO-to-NO2 (nitric oxide to nitrogen dioxide) converter and a photoacoustic sensor for NO2. The latter has been described in “Relaxation effects and high sensitivity photoacoustic detection of NO2 with a blue laser diode” by Kalkman and Van Kesteren in Applied Physics B 90 (2008) p 197-200. This apparatus enables, in combination with a NO-to-NO2 converter, a detection limit of NO in the low parts-per-billion (ppb) range and a real-time measurement of the NO concentration as required for tidal breathing, but an acoustic resonator with a high quality factor is required as part of the photoacoustic sensor in order to reach this detection limit.
However, during tidal breathing, the concentrations of O2 and CO2 in the exhaled breath change and this results in a change in the speed of sound of the exhaled air. The related shift of the resonance frequency of the acoustic resonator leads to a variation in the response to NO during the exhalation.
In a paper entitled “Photoacoustic spectrometer for measuring light absorption by aerosol: instrument description” by Arnott et al. [Atmospheric Environment 33 (1999) p 2845-2852] a photoacoustic spectrometer is described which incorporates a piezoelectric disk for sound generation that can be used to determine the resonance frequency of the photoacoustic cell. This spectrometer could either be operated in a mode to determine the resonance frequency with the piezoelectric disk or be operated in a photoacoustic gas sensing mode with the light source being modulated at a fixed frequency and the piezoelectric disk switched off. For environmental air with a slowly varying composition and temperature this approach works satisfactory. However, as with the previously-described apparatus, this photoacoustic spectrometer cannot adapt to the shift of the resonance frequency that occurs during exhalation due to changes in concentration of O2 and CO2.
In principle the photoacoustic sensor can be operated at various modes of the acoustic resonator and non-interfering longitudinal and transverse modes can be chosen for photoacoustic sensing and resonance tracking. In practice, the involvement of longitudinal as well as transverse modes leads to large resonator sizes and a significant loss of sensitivity.